Chromatogram data processing method and device

ABSTRACT

Before executing a search for optimal correspondence relationship with a coarse-to-fine DP (dynamic programming) algorithm using time information of peaks appearing in a chromatogram as input data, a simplified linear correction is executed based on detection of start point and end point of the section in which the peaks are present. It is sufficient to correct only nonlinear time deviations in coarse-to-fine DP, and the space to be searched is thus narrowed down. In addition, in coarse stage DP, the number of pieces of data to be processed is reduced by selecting peaks based on peak intensity. Between coarse stage DP and fine stage DP, local inappropriate matching is eliminated by performing filtering processing in accordance with trend of time deviations over the entire chromatogram. The space to be searched in fine stage DP becomes narrow, which reduces the number of candidates to be searched and shortens the calculation time.

TECHNICAL FIELD

The present invention relates to a chromatogram data processing methodand device for processing chromatogram data obtained by chromatographicanalysis of a gas chromatogram (GC), a liquid chromatograph (LC), or thelike; more particularly, the present invention relates to a dataprocessing method and device for correcting the retention times of peaksappearing in a chromatogram.

BACKGROUND ART

In GC analysis, even if analysis is performed with the same device andunder the same conditions, there is sometimes deviation in the retentiontimes of the same component due to various factors such as fluctuationsin the carrier gas flow rate over time and column deterioration.Therefore, in order to compare a plurality of chromatograms, anoperation is required to correct the time axis so that the retentiontimes of the same component are aligned roughly uniformly prior to thiscomparison. Although the correction of the time axis is easy if thedeviation in the retention times is completely linear, deviations inretention times more often than not have nonlinearity. As one means forcorrecting the time axis to accommodate such nonlinear deviations inretention times, algorithms based on dynamic programming (abbreviatedbelow as “DP”) have been proposed conventionally (see Non-PatentDocument 1 and Patent Document 1).

A DP algorithm that is typically used conventionally is a technique forcoordinating a reference signal (reference chromatogram signal) servingas a standard and a target signal (target chromatogram signal) for whichthe time axis has been distorted nonlinearly, using the degree ofdistortion in time and the degree of matching of the intensities atcorresponding points as a cost function, and finding a correspondencerelationship between the reference signal and the target signal in whichthe calculated cost is minimized. If such a correspondence relationshipcan be found, it is possible to correct deviations in retention times bynonlinearly expanding and contracting the time axis of the target signalusing the correspondence relationship.

Here, for the purpose of the explanation, the reference signal will bedefined as A, and a sample point at each time of the reference signal Awill be expressed as A(n) (where n is a positive integer). Similarly,the target signal will be defined as B, and a sample point at each timeof the target signal B will be expressed as B(n). A method for searchingfor the optimal (most favorably matching) correspondence relationship intypical DP is as follows (see FIG. 8).

[1] Taking into consideration the range of commonsense time fluctuations(taking into consideration the maximum values of various fluctuations),the sample point of the target signal B corresponding to the samplepoint A(1) of the reference signal A may correspond to “no correspondingpoint” or to target signal B(1) to B(3), for example.

[2] Depending on where in the aforementioned range the sample point ofthe target signal B corresponding to the sample point A(1) of thereference signal A lies, the group of sample points of the target signalB to which the next sample point A(2) of the reference signal A maycorrespond will respectively differ. For example, if the sample point ofthe target signal B corresponding to the sample point A(1) of thereference signal A is B(1), the group of sample points of the targetsignal B to which the next sample point A(2) may correspond becomes “nocorresponding point” or target signal B(2) to B(4), and if the samplepoint of the target signal B corresponding to the sample point A(1) ofthe reference signal A is B(2), the group of sample points of the targetsignal B to which the next sample point A(2) may correspond becomes “nocorresponding point” or target signal B(3) to B(5).

Accordingly, as shown in FIG. 8, the potentially corresponding samplepoints increase like a tree diagram as n of the sample point A(n)increases—that is, as time passes.

Assuming from a commonsense standpoint that there are m potentiallycorresponding candidates for each sample point when searching for anoptimal correspondence relationship as described above (m=4 in the caseof the example shown in FIG. 8), if the chromatogram consists of datafor n sample points in total, the number of paths (that is, candidatesfor a correspondence relationship over the entire chromatogram) derivedis approximately m to the n^(th) power. Accordingly, the order of thenumber of candidates for a correspondence relationship between thereference signal A and the target signal B is O (m^(n)), and it isnecessary to calculate the cost of each candidate and select thecandidate with the lowest cost.

However, there are limitations to the amount of calculations that can beprocessed due to limitations in the performance of the computer used forcalculation or the calculation time, so it is not realistic to performcost calculations by searching for all of an enormous number ofcandidates as described above. Therefore, a technique is ordinarily usedin which the final number of candidates is limited to x candidates byleaving behind only the top x candidates at each stage of the search anddeleting all other data. Such a technique is typically called beamlimiting with a beam width x. Although the required processing time isshortened as the beam width x is narrowed, if the beam width x is madeunnecessarily narrow, there is an increased probability of falling intoa localized solution in which the matching in only the first half of thesearch is satisfactory and the matching in the second half is poor, andthe method is typically weak with regard to noise and the like.Conversely, in order to provide resistance (robustness) against suchnoise, it is necessary to allow an enormous amount of time forcalculation processing.

That is, when applying a typical DP algorithm such as that described inNon-Patent Document 1 or Patent Document 1 to the correction of the timeaxis of a chromatogram, it is not possible to appropriately match thetarget signal to the reference signal in a realistic amount ofcalculation processing time under unfavorable conditions such as a largenumber of peaks appearing in the chromatogram due to a large number ofcontained components, a large number of peaks due to poor S/N of theobtained signal, or extremely large fluctuations over time, which leadsto the risk that the time axis may be corrected inaccurately. Inparticular, the probability that it will not be possible to accuratelycorrect the time axis increases substantially in cases in which thereare large fluctuations over time due to column replacement in GCanalysis or cases in which a sample containing an enormous number ofcomponents such as gasoline or a perfume is analyzed.

PRIOR ART DOCUMENTS

-   PATENT DOCUMENT 1—International Publication WO 2004/090526 Pamphlet-   PATENT DOCUMENT 2—Japanese Unexamined Patent Application Publication    H5-181498-   NON-PATENT DOCUMENT 1—Pravdova (V. Pravdova) and 2 others, “A    comparison on two algorithms for warping of analytical signals,”    Analytical Chimica Acta, 456, 2002, p. 77-92-   NON-PATENT DOCUMENT 2—Hiromitsu Miyazaki and 2 others, “Elastic    matching algorithm for images based on coarse-to-fine DP,”    Proceedings of the Meeting on Image Recognition and Understanding    (MIRU2004), July 2004

SUMMARY OF THE INVENTION

The present invention was conceived in order to solve the problemsdescribed above, and the main purpose of the present invention is toprovide a chromatogram data processing method and device capable ofcorrecting the time axis of a chromatogram within a reasonableprocessing time and with high precision even under unfavorableconditions such as a large number of contained components (number ofpeaks), large amounts of noise, and large fluctuations over time. The“chromatograms” described here include total ion current chromatogramsand extracted ion chromatograms (mass chromatograms) obtained with achromatograph mass spectrometer.

A representative technique known for increasing speed in DP iscoarse-to-fine DP, which reduces both n and m in the number ofcandidates O (mn) by dividing the DP algorithm processing into twostages—a broad candidate search and a detailed candidate search. Forexample, in Patent Document 2, a technique which utilizes coarse-to-fineDP for voice recognition is disclosed. In Non-Patent Document 2, amethod of utilizing coarse-to-fine DP for the recognition of imagepatterns with variations is proposed. In general, voice signals or imagesignals have the property that there is a high correlation between asignal value at a given position and a signal value at a position nearbytemporally or spatially. Therefore, applying coarse-to-fine DP iscomparatively easy. In contrast, in the case of chromatogram signals,there is virtually no correlation between a given peak and another peaknearby temporally, and it is not possible to directly use thecoarse-to-fine DP for voice or images as described above. Accordingly,the inventor of this application conceived of the invention of thisapplication as a result of introducing the coarse-to-fine DP techniqueto the correction of the time axis of a chromatogram while addingprocessing so as to minimize the amount of calculations of DP byutilizing the properties of chromatogram signals.

Specifically, the first invention, which was conceived in order to solvethe problems described above, is a chromatogram data processing methodwhich, for chromatogram data obtained by a chromatograph devicecomprising a separation part for separating various components containedin a sample in the time direction and a detector for detecting a samplewith separated components, corrects the time axis of a referencechromatogram serving as a standard so as to align the time axis of atarget chromatogram with the time axis of the reference chromatogram,the method comprising:

a) a linear correction step for eliminating linear time variation fromthe target chromatogram using peaks detected in the referencechromatogram and the target chromatogram;

b) a coarse searching step for searching for candidates for acorrespondence relationship between the reference chromatogram and thetarget chromatogram in a coarse stage by selecting peaks for therespective reference chromatogram and target chromatogram based on therespectively detected peak intensities in the target chromatogram andthe reference chromatogram after linear correction by the linearcorrection step and executing matching by a dynamic programmingalgorithm focusing on the retention times of the selected peaks;

c) a fine searching step for searching for a correspondence relationshipbetween the reference chromatogram and the target chromatogram in a finestage by adding the peaks eliminated in the coarse searching step andthen executing matching by a dynamic programming algorithm focusing onthe retention times of the peaks for the candidates for a correspondencerelationship in the coarse stage extracted in the coarse searching step;and

d) a correction processing step for correcting the time axis of thetarget chromatogram based on the correspondence relationship between thereference chromatogram and the target chromatogram extracted in the finesearching step.

In addition, the second invention is a device for implementing thechromatogram data processing method of the first invention which, forchromatogram data obtained by a chromatograph device comprising aseparation part for separating various components contained in a samplein the time direction and a detector for detecting a sample withseparated components, corrects the time axis of a reference chromatogramserving as a standard so as to align the time axis of a targetchromatogram with the time axis of the reference chromatogram, thedevice comprising:

a) a linear correction means for eliminating linear time variation fromthe target chromatogram using peaks detected in the referencechromatogram and the target chromatogram;

b) a coarse searching means for searching for candidates for acorrespondence relationship between the reference chromatogram and thetarget chromatogram in a coarse stage by selecting peaks for therespective reference chromatogram and target chromatogram based on therespectively detected peak intensities in the target chromatogram andthe reference chromatogram after linear correction by the linearcorrection means and executing matching by a dynamic programmingalgorithm focusing on the retention times of the selected peaks;

c) a fine searching means for searching for a correspondencerelationship between the reference chromatogram and the targetchromatogram in a fine stage by adding peaks eliminated by the coarsesearching means and then executing matching by a dynamic programmingalgorithm focusing on the retention times of the peaks for thecandidates for a correspondence relationship in the coarse stageextracted by the coarse searching means; and

d) a correction processing means for correcting the time axis of thetarget chromatogram based on the correspondence relationship between thereference chromatogram and the target chromatogram extracted by the finesearching means.

One of the most significant causes of deviations in retention timearising in a chromatogram is column degradation, but although there issome degree of fluctuation, deviations in retention time caused by thisare primarily temporally linear deviations. That is, the deviations aresuch that the time axis of a target chromatogram is expanded by a factorof p (or reduced to 1/p) on the whole with respect to the time axis of areference chromatogram and is further shifted on the whole by q. Withthe chromatogram data processing method and device of the presentinvention, the linear time deviations described above are reduced inadvance by means of linear correction processing in the linearcorrection step before coarse-to-fine DP is executed. This makes itsufficient to correct only nonlinear retention time deviations incoarse-to-fine DP performed subsequently, which makes it possible toperform matching with sufficient robustness even with a limited beamwidth—that is, even if the searching space is narrowed.

In the typical coarse-to-fine DP described above, data of low timeresolution is first generated by re-sampling calculation data, andcoarse-to-fine DP is performed to reduce the number of data points (n)using this as input data. After m is then reduced by applying therestriction of not significantly going against the optimalcorrespondence relationship (matching) obtained at the low timeresolution and then performing DP processing in the fine stage at theoriginal (prior to re-sampling) time resolution. However, in the case ofa chromatogram signal, the actual information held by the originalsignal is lost due to simple re-sampling. The important information inthe case of a chromatogram signal is the positions (times) of the topsof peaks, so the positions (times) of detected peaks are used as inputdata for DP.

However, when there is a large number of contained components, thenumber of peaks also increases, and peaks caused by noise also appear inthe chromatogram. Therefore, in the coarse searching step, the number ofpieces of data to be processed is reduced and the effects of noise aresimultaneously reduced by selecting only peaks with a particularly highprobability of being useful for correction in order of intensity, forexample, and using the peaks as input data for DP. The peak intensityused for this peak extraction may use the peak height and/or the peakarea. As a result of the coarse searching step described above,candidates are found for a correspondence relationship between each peakextracted in the reference chromatogram and each peak extracted in thetarget chromatogram. That is, for each peak extracted in the referencechromatogram, one or a plurality of candidates of corresponding peaks inthe target chromatogram are given.

Next, in the fine searching step, the candidates for a correspondencerelationship are narrowed down by executing matching based on thecandidates found in the coarse searching step, including the peaksexcluded previously due to low intensity. For example, for the peaks ina reference chromatogram for which at least one corresponding peakcandidate has been given in the coarse searching step, if one of thecandidates is given as a candidate in the fine searching step, thecandidate is considered to be the optimal solution and the othercandidates are discarded. On the other hand, for peaks in a referencechromatogram with no corresponding peak candidates in the coarsesearching step, a cost calculation for fine searching should be madeusing the provisional position (time) found by directly correcting thecandidate at the closest position temporally.

With DP using two stages (coarse and fine), it is possible to find themost reliable correspondence relationship between each peak in thereference chromatogram and each peak in the target chromatogram. Next,in the correction processing step, the time axis of the targetchromatogram is corrected based on the correspondence relationshipdescribed above. As a result, the entire signal waveform of the targetchromatogram is corrected rather than only the positions of the tops ofthe peaks using the reference chromatogram as a standard.

The chromatogram data processing method of the first invention shouldalso have a filtering step which, after the execution of the coarsesearching step and before the execution of the fine searching step, usesthe overall trend of matching as an evaluation criterion and removesmatching results which do not conform to the evaluation criterion. As anoverall matching trend, a statistical value of the overall amount offluctuation should be used. For example, the standard deviation of theamount of fluctuation may be found, and this standard deviation can beused as an evaluation criterion.

As a result, candidates which are invalid as indicated by the overalltrend can be removed in advance from the peak correspondence candidatesgiven in the coarse searching step. Therefore, it is possible toeffectively reduce the amount of calculation by cutting the number ofcandidates for a correspondence relationship, and it is also possible toincrease the searching precision in the DP of the fine stage.

As one mode of the chromatogram data processing method of the firstinvention, the linear correction step may find a coefficient for linearcorrection by extracting a corresponding time range between thereference chromatogram and the target chromatogram using the intensitycorrelations and time relationships of a plurality of peaks close to oneanother in the time direction, investigating the degree of matching ofpeaks when performing linear correction while assuming combinations ofthe time ranges, and selecting the combination of time ranges whichdemonstrates the best match. Here, it is preferable to extract timeranges respectively corresponding to the head part and the tail end partof the reference chromatogram and the target chromatogram.

In addition, as a measure indicating the degree of matching of peaks inthe linear correction step, for each peak in the reference chromatogram,the sum of the absolute values of time differences of a single peak inthe reference chromatogram and a peak positioned closest to theaforementioned peak and falling within a certain intensity ratio rangewith respect to the intensity of the peak in the reference chromatogramin the target chromatogram after linear correction is performed underthe assumptions described above may be used. As a result, it is possibleto realize linear correction with high precision using comparativelysimple operations.

With the chromatogram data processing method and device of the presentinvention, in order to correct the time axis of a chromatogram,coarse-to-fine DP which is improved so as to conform to the propertiesof chromatogram signals and situations in which time fluctuations ariseis used, and correction is performed by removing linear time deviationsprior to this coarse-to-fine DP, so it is possible to sufficiently matchthe target chromatogram to the reference chromatogram while efficientlyreducing the number of candidates for a correspondence relationship. Asa result, it is possible to correct the time axis in a sufficientlyshort period of time for practical applications and with high precisioneven under unfavorable conditions such as a large number of peaks due toa large number of components contained in a sample, poor signal S/N, andlarge fluctuations over time, for example. Accordingly, it becomespossible, for example, to compare multiple chromatograms with goodprecision.

In addition, since data processing has sufficient robustness, it ispossible to process data obtained from various samples without changingthe parameters required for data processing such as the weight of thecost function or the beam width at the time of coarse-to-fine DP inaccordance with the types of samples or the analysis conditions.Therefore, the burden of the operator at the time of data processing isreduced, and the processing throughput is also improved.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an overall schematic diagram of a GC device to which thechromatogram data processing device of the present invention is applied.

FIG. 2 is a flowchart showing the processing procedure of the time axiscorrection method characteristic to the present invention.

FIG. 3 is a flowchart of simple linear correction in FIG. 2.

FIG. 4 is an explanatory diagram of the concept of simple linearcorrection.

FIG. 5 is an explanatory diagram of the processing of simple linearcorrection.

FIG. 6 is a flowchart of the coarse stage DP of FIG. 2.

FIG. 7 is an explanatory diagram of the concept of mistaken candidatefiltering processing in FIG. 2.

FIG. 8 is an explanatory diagram of typical DP.

FIG. 9 is a drawing showing the results of a simulation for verifyingthe effects of the time axis correction method characteristic to thepresent invention.

DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS

An embodiment of a gas chromatograph (GC) device using a chromatogramdata processing device implementing the chromatogram data processingmethod of the present invention will be described with reference to theattached drawings.

FIG. 1 is a schematic block diagram of the GC device of this embodiment.In FIG. 1, a carrier gas is supplied at a constant flow rate to a column2 from a sample introducing part 1 including a sample vaporizing chamberor the like, and when a sample is infused into the sample introducingpart 1, the sample is carried by the carrier gas flow and introducedinto the column 2. Various components in the sample are separated in thetime direction while the sample passes through the column 2 and are thensequentially eluted from the column 2 outlet and introduced into adetector 3. The detector 3 is a flame ionization detector (FID) or amass spectrometer, for example, which constantly outputs a detectionsignal corresponding to the amount of the introduced sample components.This signal is converted to a digital value by an A/D converter 4 andinputted into a data processing part 5. The data processing part 5comprises a chromatogram data storage part 51, a time axis correctionoperation processing part 52, a chromatogram creation/drawing part 53,and the like, and the created chromatogram is displayed on a displaypart 6.

The main part of the data processing part 5 is a personal computer, andthe functions of each of the parts described above can be realized byoperating dedicated data processing software installed in advance on thecomputer.

When chromatogram data is obtained by executing GC analysis of the samesample under the same analysis conditions using this GC device, theretention times of the same sample components will ideally always be thesame. However, in actuality, fluctuations in the time axis arise due tovarious factors such as changes in the interactions between the samplecomponents and the inside wall of the column 2 due to the degradation ofthe column 2 over time, temporal fluctuations in the flow rate of thecarrier gas supplied to the column 2 from the sample introducing part 1,and temporal fluctuations in the heating rate of the column oven (notshown) in which the column 2 is housed, and it is often the case thatthe retention times for the same sample components are not constant.This becomes problematic when comparing a plurality of chromatograms, inparticular. Therefore, the GC device of this embodiment is configured soas to correct the time axis of the chromatogram obtained by GC analysisby means of the following such time axis correction processing.

FIG. 2 is a flowchart showing the general procedure of the time axiscorrection processing executed by the time axis correction operationprocessing part 52. The time axis correction processing described hereis processing for correcting the time axis of a target chromatogramobtained by GC analysis so as to match the time axis of a referencechromatogram stored in the chromatogram data storage part 51 using thereference chromatogram as a standard. The reference chromatogram and thetarget chromatogram are fundamentally obtained by analyzing the sametype of sample.

As a procedure for correction processing, peak detection is firstperformed for the reference chromatogram and the target chromatogram,respectively, and the positions (times) and intensities (heights and/orareas) of the tops of peaks are obtained as peak information (step S1).The time information of the peaks detected here serve as input data forthe coarse-to-fine DP described below.

Next, simple linear correction processing is executed in order toeliminate linear retention time deviations contained in the targetchromatogram (step S2). As a result of this simple linear correction,the linear component including expansion/contraction by a factor of p inthe time axis direction and a shift by time q is almost completelyeliminated in the target chromatogram, and nonlinear retention timedeviations are left behind. In actuality, linear correction should beperformed for each peak in the target chromatogram so as to amend thetime information of the peaks. Of course, it is also possible to correctlinear time deviations in coarse-to-fine DP, but since linear timedeviations are ordinarily substantially larger than nonlinear timedeviations, the search space at the time of DP becomes quite large iflinear and nonlinear deviations are mixed (overlapping). In contrast,the search space can be narrowed by eliminating linear time deviationsin advance.

After simple linear correction, the number of peaks is reduced to aprescribed number by selecting peaks based on the intensity informationof each peak in the reference chromatogram and the target chromatogram,respectively. The time information (time information after linearcorrection for the target chromatogram) of peaks after the number hasbeen substantially reduced in comparison to the original number of peaksdue to this selection is then used as input data, and a search isperformed for candidates for a correspondence relationship between thereference chromatogram and the target chromatogram by performingmatching based on a DP algorithm in the coarse stage (step S3).

After the candidate search by coarse stage DP is completed and beforethe next search by fine stage DP is performed, matching presumed to beobviously erroneous is eliminated from the candidates given in thesearch of the coarse stage by filtering processing using the validity ofcorrection from the perspective of the overall trend as a criterion(step S4). As a criterion for assessing whether matching is erroneous, astatistical value of the overall amount of fluctuation in timedeviations, for example, may be used. The number of candidates to besearched can be reduced by this filtering processing.

Next, using the matching results of coarse stage DP, peaks which werenot selected in the peak selection described above—that is, peaks thatwere not considered in coarse stage DP—are added, and the candidates fora correspondence relationship given in coarse stage DP are ultimatelynarrowed down to one candidate by performing matching based on the DPalgorithm of the fine stage (step S5). If an optimal correspondencerelationship—that is, one involving the lowest cost—of the targetchromatogram with respect to the reference chromatogram is found as aresult of the search for candidates based on coarse-to-fine DP, a signalfor which each sample point of the target chromatogram is moved—that is,a signal with a corrected time axis—is found by warp processing based onthis result (step S6). As a result, chromatogram data in which theretention time deviations contained in the target chromatogram arecorrected is obtained.

The series of processes described above will be described in detail withfocus on the processing characteristic to the present invention.

Simple Linear Correction

The main cause of retention time deviations in a chromatogram is thedegradation of the column 2, and although there is some degree offluctuation, most retention time deviations caused by this are linear.That is, the general trend of the time deviations of the targetchromatogram with respect to the reference chromatogram is rectilinear.Therefore, by eliminating linear retention time deviations beforeattempting to correct the time axis by DP, it is possible to reduce theburden of correction by DP and improve the correction precision. FIG. 3is a flowchart showing the procedure for simple linear correctionprocessing. FIG. 4 is an explanatory diagram of the concept of simplelinear correction. FIG. 5 is an explanatory diagram of the processing ofsimple linear correction.

As shown in FIG. 4, the linear component and the nonlinear componentordinarily overlap in the time deviations of a chromatogram, but thelinear components are often dominant. It can be seen that if the linearcomponent is not eliminated, the amount of deviation that must becorrected by coarse-to-fine DP is d2, whereas if the linear component iseliminated, the amount of deviation that must be corrected bycoarse-to-fine DP is only d1.

The linear component of time deviations can be calculated from the startpoint and end point of the section where peaks are present in thechromatogram, but start point/end point detection with high resistanceto noise and the like is necessary for this purpose. Here, by using aplurality of peaks appearing in the vicinity of one another temporallyas one group and evaluating the similarity between the referencechromatogram and the target chromatogram, the start point and the endpoint of the section where the peaks are present in the twochromatograms are detected. In addition, the section where the peaks arepresent in the target chromatogram is expanded/contracted and shifted inthe time axis direction so that the start point and end point of thesection where the peaks are present in the target chromatogram match thestart point and end point of the section where the peaks are present inthe reference chromatogram.

That is, candidates for the front and the tail end are first extractedfor the reference chromatogram and the target chromatogram,respectively, using a prescribed range in the vicinity of the startpoint and a prescribed range in the vicinity of the end point of thesection where the peaks are present (step S21). Specifically, as shownin FIG. 5, three temporally consecutive peaks (triple peaks) areextracted, and the correlation coefficient α of the intensities of thethree peaks and the ratio β=T1/T2 of the time interval T1 between thefirst peak and the second peak and the time interval T2 between thesecond peak and the third peak are found. The correlation coefficient αand the time interval ratio β are parameters for assessing theconformity (similarity) of the triple peaks in the referencechromatogram and the triple peaks in the target chromatogram. Theconformity of the triple peaks on the start point side of the referencechromatogram and the triple peaks on the start point side of the targetchromatogram is then evaluated using the correlation coefficient α andthe time interval ratio β, and peaks with a high probability of matchingare selected and designated as candidates for the front end. Similarly,peaks with a high probability of matching among the triple peaks on theend point side of the reference chromatogram and the triple peaks on theend point side of the target chromatogram are selected and designated ascandidates for the tail end.

Next, one of each of the candidates (triple peaks) for the front end andthe candidates (triple peaks) for the tail end extracted in step S21described above is selected, and a trial run of linear correction isactually performed on the target chromatogram under those conditions toassess the degree of matching of the peaks in the subsequent targetchromatogram and the reference chromatogram (step S22). The index forestimating the degree of matching of the peaks of the two chromatogramsuses the sum of the distances (times) between the peaks in the targetchromatogram located at the nearest positions temporally to each peakappearing in the reference chromatogram and having intensities such thatthe ratios of the intensities of the peaks fall within a certain rangeas an evaluation function. An evaluation of peak conformity is executedusing the same evaluation function for all combinations of candidates(step S3), and a combination of candidates at the front and the tail endfor which the evaluation function is smallest is selected (step S24). Inactuality, in order to simplify the calculations, an evaluation functiondetermined by adding the evaluation function of the degree of conformitydescribed above and an evaluation function indicating the degree towhich candidates are at the front or the tail end should be used.

The start point and the end point of the section where the peaks arepresent in the reference chromatogram and the target chromatogram areestablished by the processing described above, so the parameters forlinear correction (specifically, the expansion/contraction rate p andthe amount of shift q) are thereby calculated (step S25), and theposition of each peak in the target chromatogram is corrected inaccordance with the parameters (step S26). As a result, the linearcomponent of time deviations contained in the target chromatogram isalmost completely eliminated.

[Step S3] Search by Coarse Stage DP

FIG. 6 is a flowchart showing the processing procedure for coarse stageDP. In coarse stage DP, in order to reduce the amount of data to beprocessed, the data is first simply thinned out at a constant ratio inorder to peak intensity, and processing is performed whereby peaks withan intensity equal to or less than a certain relative intensity areconsidered highly likely to be noise and are removed. As a result, peakswhich can be presumed to be significant to correction are selected, andthe number of peaks is limited to a prescribed number (step S31).Matching based on a DP algorithm is then executed using the times of thepeaks of the reference chromatogram and the target chromatogram as inputdata. That is, the peak correspondence candidates extracted in thetarget chromatogram are given in order from the earliest peaks for peaksextracted in the reference chromatogram, and when a plurality ofcandidates are given, the search is repeated so that the next peakcorrespondence candidate is given for each candidate. Accordingly, asshown in FIG. 8, the candidates expand in a tree shape (step S32).

At this time, by restricting the expansion of candidates to a time rangetaking into consideration the maximum assumed value of nonlinear timedeviations, the number of candidates given at each peak point isrestricted. As described above, since the linear time deviations areeliminated in advance, it is possible to avoid situations in whichlegitimate candidates are eliminated even if this restriction is madestrict (even if the beam width is narrowed).

Next, the cost is calculated for each of the retrieved candidates for acorrespondence relationship (step S33).

The cost function in coarse stage DP is as follows.

(1) A value determined by multiplying the logarithm of the intensityratio of corresponding peaks by a certain constant. However, if there isno corresponding peak, this is a value determined by adding a certainconstant to the peak intensity for every skipped peak.

(2) Amount of time fluctuation: Absolute value of the time differencebetween a peak in the reference chromatogram and a peak in the targetchromatogram

(3) Difference in the amount of time fluctuation: Since most timefluctuations occur gradually, the difference in the amount of timefluctuation should assume a value close to zero. Therefore, as a valuecorresponding to the mean amount of time fluctuation, the absolute valueof the difference between a value determined by applying a low-passfilter to the amount of time fluctuation and the present timefluctuation at the corresponding peak is used.

(4) Intensity ratio difference: There is a very strong correlationbetween the intensities of each of the peaks in the referencechromatogram and the target chromatogram after matching, and theintensity ratio is ideally constant. Therefore, as a value correspondingto the mean of the logarithm of the intensity ratio, the absolute valueof the difference between a value determined by applying a low passfilter to the logarithm of the intensity ratio and the logarithm of theintensity ratio at the present corresponding peak is used.

In actuality, a cost function is obtained by multiplying with a constantafter performing a predetermined gamma correction on (1) to (4) above.

If the cost calculation is complete for all of the candidates for acorrespondence relationship between the reference chromatogram and thetarget chromatogram, the candidate with the lowest cost is selected, andthis is determined as the optimal match of coarse stage DP (step S34).

[Step S4] Filtering Processing

Although DP is excellent for local matching, there are cases in whichmatching is performed so as to deviate from the validity of correctionas indicated by the overall trend of the chromatogram. Therefore, asshown in FIG. 7, the standard deviation of the time deviation at eachpeak point is calculated for the correspondence relationship determinedas an optimal match, and if there is any deviation from the standarddeviation, the matching of the peak in question is eliminated.

[Step S5] Search by Fine Stage DP

Next, after the search space is narrowed down using the matching resultsobtained by coarse stage DP, matching is executed using a DP algorithmincluding peaks which were excluded at the time of coarse stage DP. Atthis time, the time fluctuation in fine stage DP assumes a value closeto the time fluctuation found in coarse stage DP, so the gammacorrection and constant applied to the cost function of the results ofcoarse stage DP are changed, and the cost of the degree of divergencefrom the matching results of coarse stage DP is further added asfollows.

(1) For a peak in the reference chromatogram with a match in coarsestage DP, the cost is considered to be infinite if the matching does notconform in fine stage DP, and this candidate is discarded.

(2) For a peak in the reference chromatogram with no match in coarsestage DP, the absolute value of the time deviation from the timedetermined by the linear interpolation of the result of matching incoarse stage DP (temporally close peak) is used as the cost of thedegree of divergence.

Accordingly, the correspondence of a matching peak in coarse stage DP isconsidered accurate, and an appropriate correspondence is determined forpeaks not used in coarse stage DP. As a result, it is possible todetermine an optimal correspondence relationship between the finalchromatogram and the target chromatogram.

FIG. 9 is a drawing showing the processing results when time axiscorrection is executed using the chromatogram data processing method ofthe present invention. As shown in this figure, it can be seen that thecorrected target chromatogram closely matches the referencechromatogram.

All of the embodiments described above are merely examples of thepresent invention, and it goes without saying that appropriatemodifications, amendments, and additions within the scope of the gist ofthe present invention are also included in the scope of the patentclaims of this application.

EXPLANATION OF SYMBOLS

1 . . . sample introducing part

2 . . . column

3 . . . detector

4 . . . A/D converter

5 . . . data processing part

51 . . . chromatogram data storage part

52 . . . time axis correction operation processing part

53 . . . chromatogram creation/drawing part

6 . . . display part

What is claimed is:
 1. A chromatogram data processing method forcoordinating a time axis of a reference chromatogram serving as astandard so that a time axis of a target chromatogram is aligned withthe time axis of the reference chromatogram, comprising: a datareceiving step for receiving target chromatogram data from achromatograph device including a separation part for separating variouscomponents contained in a sample in the time direction and a detectorfor detecting a sample with separated components, a linear correctionstep for eliminating linear time variation from the target chromatogramusing peaks detected in the reference chromatogram and the targetchromatogram; a coarse searching step for searching for candidates for acorrespondence relationship between the reference chromatogram and thetarget chromatogram in a coarse stage by selecting peaks for therespective reference chromatogram and target chromatogram, the selectedpeaks being selected based on intensity information for each of therespectively detected peaks in the target chromatogram and the referencechromatogram after linear correction by said linear correction step, anddetermining the candidates in the coarse stage by executing matching bya dynamic programming algorithm focusing on the retention times of theselected peaks, wherein peaks not selected by said selecting areeliminated from consideration during said matching; a fine searchingstep for searching for a correspondence relationship between thereference chromatogram and the target chromatogram in a fine stage byadding the peaks that were eliminated from consideration in said coarsesearching step and then executing matching by a dynamic programmingalgorithm focusing on the retention times of peaks corresponding to thecandidates determined in said coarse searching step and the peaks thatwere eliminated from consideration in said coarse searching step, todetermine the correspondence relationship by verifying accuracy of thecandidates determined in said coarse searching step and determining anappropriate correspondence for the peaks that were eliminated fromconsideration in said coarse searching step; and a correction processingstep for correcting the time axis of the target chromatogram so as toalign the time axis of the target chromatogram with the time axis of thereference chromatogram based on the correspondence relationship betweenthe reference chromatogram and the target chromatogram determined insaid fine searching step.
 2. The chromatogram data processing methodaccording to claim 1 having: a filtering step which, after the executionof said coarse searching step and before the execution of said finesearching step, uses the overall trend of matching as an evaluationcriterion and removes matching results which do not conform to theevaluation criterion.
 3. The chromatogram data processing methodaccording to claim 1, wherein: said linear correction step finds acoefficient for linear correction by extracting a corresponding timerange between the reference chromatogram and the target chromatogramusing the intensity correlations and time relationships of a pluralityof peaks close to one another in the time direction, investigating thedegree of matching of peaks when performing linear correction whileassuming combinations of the time ranges, and selecting the combinationof time ranges which demonstrates a closest match in the intensitycorrelations and time relationships of the plurality of peaks close toone another.
 4. The chromatogram data processing method according toclaim 2, wherein: said linear correction step finds a coefficient forlinear correction by extracting a corresponding time range between thereference chromatogram and the target chromatogram using the intensitycorrelations and time relationships of a plurality of peaks close to oneanother in the time direction, investigating a degree of matching ofpeaks when performing linear correction while assuming combinations ofthe time ranges, and selecting as the target chromatogram and thereference chromatogram after linear correction the coefficient forlinear correction that provides a closest match in the intensitycorrelations and time relationships of the plurality of peaks close toone another.
 5. The chromatogram data processing method according toclaim 3, wherein: as a measure indicating the degree of matching ofpeaks in said linear correction step, for each peak in the referencechromatogram, the sum of the absolute values of time differences of asingle peak in said reference chromatogram and a peak positioned closestto the aforementioned peak and falling within a certain intensity ratiorange with respect to the intensity of the peak in said referencechromatogram in the target chromatogram after linear correction isperformed under the assumptions described above is used.
 6. Thechromatogram data processing method according to claim 4, wherein: as ameasure indicating the degree of matching of peaks in said linearcorrection step, for each peak in the reference chromatogram, the sum ofthe absolute values of time differences of a single peak in saidreference chromatogram and a peak positioned closest to theaforementioned peak and falling within a certain intensity ratio rangewith respect to the intensity of the peak in said reference chromatogramin the target chromatogram after linear correction is performed underthe assumptions described above is used.
 7. A chromatogram dataprocessing device for coordinating a time axis of a referencechromatogram serving as a standard so that a time axis of the targetchromatogram is aligned with the time axis of the referencechromatogram, comprising: a chromatograph device comprising a separationpart for separating various components contained in a sample in the timedirection and a detector for detecting a sample with separatedcomponents, the chromatograph device providing target chromatogram data;a linear correction means for eliminating linear time variations fromthe target chromatogram using peaks detected in the referencechromatogram and the target chromatogram; a coarse searching means forsearching for candidates for a correspondence relationship between thereference chromatogram and the target chromatogram in a coarse stage byselecting peaks for the respective reference chromatogram and targetchromatogram, the selected peaks being selected based on intensityinformation for each of the respectively detected peaks in the targetchromatogram and the reference chromatogram after linear correction bysaid linear correction means, and determining the candidates in thecoarse stage by executing matching by a dynamic programming algorithmfocusing on the retention times of the selected peaks, wherein peaks notselected by said selecting are eliminated from consideration by saidcoarse searching means; a fine searching means for searching for acorrespondence relationship between the reference chromatogram and thetarget chromatogram in a fine stage by adding peaks that were eliminatedfrom consideration by said coarse searching means and then executingmatching by a dynamic programming algorithm focusing on the retentiontimes of peaks corresponding to the candidates determined by said coarsesearching means and the peaks that were eliminated from consideration bysaid coarse searching means, to determine the correspondencerelationship by verifying accuracy of the candidates determined by saidcoarse searching means and determining an appropriate correspondence forthe peaks that were eliminated by said coarse searching means; and acorrection processing means for correcting the time axis of the targetchromatogram so as to align the time axis of the target chromatogramwith the time axis of the reference chromatogram based on thecorrespondence relationship between the reference chromatogram and thetarget chromatogram determined by said fine searching means.